Immobilizing objects in the body

ABSTRACT

Stabilizing an object in the body of a patient involves the injection of a lower critical solution temperature (LCST) material or other flowable material into the body of the patient so that the material contacts the object. The LCST material or other flowable material then forms a gel in the body such that the object is contained at least partially within the gel and thereby stabilized by the gel such that the object can then be easily fragmented within the body and/or retrieved from the body.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This is a continuation-in-part of U.S. patent application Ser.No. 09/795,635, filed on Feb. 28, 2001, the entire disclosure of whichis incorporated by reference herein.

TECHNICAL FIELD

[0002] This invention generally relates to medical instruments andmethods for retrieving material from within a body. More particularly,the invention relates to retrieval methods, devices, and compositionsfor stabilizing and removing stones such as urinary tract stones, gallstones, and other objects found in the body.

BACKGROUND INFORMATION

[0003] Medical retrieval devices generally are used to retrievebiological and foreign material, such as kidney stones and othercalculi, from the body of a patient. Such medical retrieval devices maybe used with an endoscope or a laparoscope. The use of such devices tocapture foreign material like stones is made difficult by the freedom ofmovement of the stones within the body. A stone may dislodge from itsresting place when contacted by a retrieval device. This may cause thestone to move into an area of the body that renders the stoneinaccessible or undetectable, thus preventing the capture and removal ofthe stone.

[0004] Larger stones often need to be shattered because their sizeprohibits non-surgical removal from the body. Shattering a stone (by,for example, light, chemical, or physical energy) can disperse theresulting stone fragments from the original location of the stone. Stonefragments that are not removed from the body can form the nuclei for theformation of new stones. The dispersal of the fragments caused by theshattering process can cause fragments to move into inaccessible orunknown areas of the body, thus preventing or interfering with thecapture and removal of the fragments.

SUMMARY OF THE INVENTION

[0005] It is an object of the invention to facilitate the capture andremoval of objects located within the body. The invention generallyincludes the use of a material or materials that exist in liquid formand is transformed into a gel inside the body of a patient. In oneaspect, the invention generally includes the use of a material thatexists in liquid form at temperatures below about body temperature andas a gel at temperatures about at and above body temperature. Thetemperature at which the transition from liquid to gel occurs isreferred to as the lower critical solution temperature (LCST), and itcan be a small temperature range as opposed to a specific temperature.Materials appropriate for use according to the invention possess a LCSTand are referred to as LCST materials.

[0006] The methods and systems of the present invention generallyinvolve the injection of an LCST material into a cavity or space withinthe body. Once inside the body, the LCST material can contact and atleast partially contain an object. In many cases, the LCST will entirelyenvelop and surround the object. As the temperature of the LCST materialrises due to the internal temperature of the body, the LCST materialwill reach its LCST and thus transition into the gel phase. The specifictransition point or range is determined by the specific LCST materialutilized. An object in contact with the LCST material can be at leastpartially trapped and stabilized by the gel. The stabilization of theobject allows for easier capture and retrieval of the object.Stabilization of the object also allows for easier use of a lithotripsydevice for fragmenting the object because the gel holds the object inplace. Furthermore, the gel prevents the free dispersal of fragments ofthe object after the object is broken apart by the lithotripsy device.Preventing the dispersal of the fragments allows for easier capture andretrieval of the object fragments.

[0007] The invention also relates to materials other than LCST materialsthat are in a=flowable form outside of the patient's body and may betransformed into a gel form inside the patient's body. A materialincluding crosslinkable polymers may be in a flowable form and uponcontact with a crosslinking agent be transformed into gel form. The gelformed from a material including crosslinkable polymers functionssimilarly to the LCST material by contacting and stabilizing an objectin the patient's body. The gel formed from the crosslinkable polymersmay be dissolved by contact with a de-crosslinking agent. Ade-crosslinking agent weakens or removes the bonds within the network ofcrosslinkable polymers that forms the gel. Once the gel is dissolved thematerial returns to a flowable form and may be more easily removed fromthe patient's body.

[0008] Other materials related to the invention include gelatinmaterials. Gelatin materials exist in liquid form at temperatures aboveabout body temperature and as a gel at temperatures below about bodytemperature. The gelatin material is cooled after it is injected intothe patient's body in order to transform the gelatin material into a gelform. Cooling of the gelatin material can be performed by contacting thegelatin material with a liquid that is at a temperature below about bodytemperature. Water or a buffer at a temperature below about bodytemperature may be injected concurrently with the injection of thegelatin material, for example.

[0009] The invention, in one aspect, includes a method of stabilizing anobject in the body of a patient. The method includes injecting a lowercritical solution temperature material in a flowable form into the bodyof the patient to contact the object. The method further includesallowing the lower critical solution temperature material to form a gelin the body due to a temperature inside the body. The object thus iscontained at least partially within the gel and stabilized by the gel.

[0010] In one embodiment according to this aspect of the invention, themethod involves the use of the lower critical solution temperature(LCST) material that remains in the flowable form below about thetemperature inside the body of the patient. The LCST material can formthe gel about at and above the temperature inside the body of thepatient.

[0011] In other embodiments, the method can include retrieving thestabilized object from the gel and/or breaking the object into at leasttwo fragments. At least some of the fragments remain at least partiallywithin the gel and stabilized by the gel, and these fragments can thenbe retrieved from the gel.

[0012] In another aspect, the invention relates to a system forstabilizing an object in the body of a patient. The system includes alower critical solution temperature material which remains in a flowableform below about a temperature inside the body of the patient and whichforms a gel about at and above the temperature inside the body of thepatient. The system also includes a catheter for transferring the lowercritical solution temperature material into the body in the flowableform and a guide wire for introducing the catheter into the body andguiding it to about the location of the object. The system also includesa mechanism to force the lower critical solution temperature material inthe flowable form through the catheter and into the body to contact theobject. The lower critical solution temperature material gels inside thebody due to the temperature inside the body and thereby contains atleast a portion of the object within the gel to stabilize the object.One embodiment according to this aspect of the invention involves theuse of the catheter to remove the lower critical solution temperaturematerial from the body.

[0013] In still another aspect, the invention features a system forstabilizing an object in the body of a patient. The system includes alower critical solution temperature material which remains in a flowableform below about a temperature inside the body of the patient and whichforms a gel about at and above the temperature inside the body of thepatient. The system also includes a percutaneous access device fortransferring the lower critical solution temperature material into thebody in the flowable form. The system further includes a mechanism toforce the lower critical solution temperature material in the flowableform through the percutaneous access device and into the body to contactthe object. As before the lower critical solution temperature materialgels once inside the body due to the temperature inside the body andthereby contains at least a portion of the object within the gel tostabilize the object.

[0014] In one embodiment according this aspect of the invention, thepercutaneous access device comprises a needle. In some embodiments, thesystem further includes a catheter for removing the lower criticalsolution temperature material from the body. In some embodiments of thisand the prior aspects of the invention, the mechanism used to force thelower critical solution temperature material into the body comprise's asyringe.

[0015] The lower critical solution temperature material used inconnection with all aspects of the invention can comprise a blockcopolymer with reverse thermal gelation properties. The block copolymercan further comprise a polyoxyethylene-polyoxypropylene block copolymersuch as a biodegradable, biocompatible copolymer of polyethylene oxideand polypropylene oxide. Also, the lower critical solution temperaturematerial can include a therapeutic agent such as an anti-angiogenicagent.

[0016] In another aspect, the invention relates to a method forstabilizing an object in a patient's body. The method includes injectinga first material, which includes a crosslinkable polymer in a flowableform, into the patient's body to contact an object. The method alsoincludes contacting the first material with a second material. Thesecond material includes a crosslinking agent, and the first materialand second material, upon contact, form a gel in the patient's body. Themethod also includes stabilizing the object in the patient's body byenabling the gel to contact the object.

[0017] In an embodiment of the method, the first material includes oneor more of an anionic crosslinkable polymer, a cationic crosslinkablepolymer, or a non-ionically crosslinkable polymer. In other embodimentsof the method, the first material includes one or more of polyacrylicacids, polymethacrylic acid, alginic acid, pectinic acids, sodiumalginate, potasium alginate, carboxy methyl cellulose, hyaluronic acid,heparin, carboxymethyl starch, carboxymethyl dextran, heparin sulfate,chondroitin sulfate, polyethylene amine, polysaccharides, chitosan,carboxymethyl chitosan, cationic starch or salts thereof.

[0018] In another embodiment of the method, the second material includesone or more of an anionic crosslinking ion, a cationic crosslinking ion,or a non-ionic crosslinking agent. In other embodiments of the method,the second material includes one or more of phosphate, citrate, borate,succinate, maleate, adipate, oxalate, calcium, magnesium, barium,strontium, boron, beryllium, aluminium, iron, copper, cobalt, lead, orsilver ions. In still other embodiments of the method, the secondmaterial includes one or more of di-vinylsulfone, polycarboxylic acids,polycarboxylic anhydrides, polyamines, epihalohydrins, diepoxides,dialdehydes, diols, carboxylic acid halides, ketenes, polyfunctionalaziridines, polyfunctional carbodiimides, polyisocyanate,glutaraldehyde, or polyfunctional crosslinkers including functionalgroups capable of reacting with organic acid groups.

[0019] In another embodiment, the method further includes the step ofretrieving the object from the gel. In yet another embodiment, themethod further includes the step of applying energy to the objectcausing it to break into at least two fragments. At least some of thefragments remain at least partially in contact with the gel andstabilized by the gel. In others embodiments of the method, the energyapplied to the object is selected from the group consisting ofmechanical, vibrational, light, chemical, and electromagnetic energy. Inother embodiments of the method, the technique for breaking the objectinto at least two fragments is selected from the group consisting ofextra-corporeal shock wave lithotripsy, intra-corporeal shock wavelithotripsy, or Holmium laser fragmentation.

[0020] In another embodiment, the method further includes the step ofretrieving at least some of the fragments from the gel. In oneembodiment, the step of retrieving some of the fragments from the gelincludes using a retrieval device to retrieve such fragments.

[0021] In yet another embodiment, the method further includes contactingthe gel with a third material that includes a de-crosslinking agent. Insome embodiments, the third material includes one or more of sodiumphosphate, sodium citrate, inorganic sulfates, ethylene diaminetetraacetic acid and ethylene dime tetraacetate, citrates, organicphosphates (e.g., cellulose phosphate), inorganic phosphates (e.g.,pentasodium tripolyphosphate, mono- and di-basic potassium phosphate,sodium pyrophosphate), phosphoric acid, trisodium carboxymethyloxysuccinate, nitrilotriacetic acid, maleic acid, oxalate, polyacrylicacid, sodium, potassium, calcium, or magnesium ions.

[0022] In another aspect, the invention relates a method of fragmentingan object in a patient's body. The method includes injecting a materialin a flowable form into the patient's body to contact an object,allowing the material to form a gel in the patient's body, andstabilizing the object in the patient's body by enabling the gel tocontact the object. The method also includes applying energy fromoutside of the patient's body that is directed towards the object. Theenergy directed towards the object breaks the object into at least twofragments. In one embodiment the energy is produced by extra-corporealshock wave lithotripsy.

[0023] In one embodiment according to this aspect of the invention, thematerial includes one or more of a crosslinkable polymer, a gelatinmaterial or a lower critical solution temperature material. In anotherembodiment, the material includes a polyoxyethylene-polyoxypropyleneblock copolymer.

[0024] In another embodiment, the method further includes retrieving thestabilized object from the gel. In yet another embodiment, the methodfurther includes breaking the object into at least two fragments. Atleast some of the fragments remain in contact with the gel. In anotherembodiment, the method further includes retrieving the at least some ofthe fragments from the gel. In one embodiment, the method furtherincludes contacting the lower critical solution temperature materialwith a degradation modulating material. In another embodiment, thedegradation modulating material is selected from the group consisting ofpluronic acid, polylactic acid, polyglycolic acid, and hyaluronic acid.

[0025] In another aspect, the invention relates to a system forstabilizing an object in a patient's body. The system includes a firstmaterial that includes a crosslinkable polymer in flowable form, and asecond material that includes a crosslinking agent. The first materialand second material, upon contact, form a gel in the patient's body. Thesystem also includes a catheter for transferring the first material andsecond material into the patient's body in flowable form, such that thegel formed by the first material and second material contacts andthereby stabilizes the object. The system also includes a guide wire forintroducing and guiding the catheter into the patient's body.

[0026] In yet another aspect, the invention relates to a system forstabilizing an object in a patient's body. The system includes a firstmaterial that includes a crosslinkable polymer in flowable form, and asecond material that includes a crosslinking agent. The first materialand second material, upon contact, form a gel in the patient's body. Thesystem also includes a percutaneous access device for injecting thefirst material and second material into the patient's body in flowableform, such that the gel formed by the first material and second materialcontacts and thereby stabilizes the object.

[0027] In embodiments according to the aspects of the invention relatingto a system, the first material includes one or more of an anioniccrosslinkable polymer, a cationic crosslinkable polymer, or anon-ionically crosslinkable polymer. In other embodiments according tothe aspects of the invention relating to a system to the first materialincludes one or more of polyacrylic acids, polymethacrylic acid, alginicacid, pectinic acids, sodium alginate, potasium alginate, carboxy methylcellulose, hyaluronic acid, heparin, carboxymethyl starch, carboxymethyldextran, heparin sulfate, chondroitin sulfate, polyethylene amine,polysaccharides, chitosan, carboxymethyl chitosan, cationic starch orsalts thereof.

[0028] In yet other embodiments according to the aspects of theinvention relating to a system, the second material includes one or moreof an anionic crosslinking ion, a cationic crosslinking ion, or anon-ionic crosslinking agent. In other embodiments according to theaspects of the invention relating to a system, the second materialincludes one or more of phosphate, citrate, borate, succinate, maleate,adipate, oxalate, calcium, magnesium, barium, strontium, boron,beryllium, aluminium, iron, copper, cobalt, lead, or silver ions. Instill other embodiments of the method, the second material includes oneor more of di-vinylsulfone, polycarboxylic acids, polycarboxylicanhydrides, polyamines, epihalohydrins, diepoxides, dialdehydes, diols,carboxylic acid halides, ketenes, polyfunctional aziridines,polyfunctional carbodiimides, polyisocyanate, glutaraldehyde, orpolyfunctional crosslinkers including functional groups capable ofreacting with organic acid groups.

[0029] The foregoing and other objects, aspects, features, andadvantages of the invention will become more apparent from the followingdescription and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In the drawings, like reference characters generally refer to thesame parts throughout the different views. Also the drawings are notnecessarily to scale, emphasis instead generally being placed uponillustrating the principles of the invention.

[0031]FIG. 1a illustrates the insertion of a distal end of a guide wireinto a kidney containing a kidney stone.

[0032]FIG. 1b illustrates the insertion of a catheter into the kidney bypassage over the guide wire of FIG. 1a.

[0033]FIG. 1c illustrates the removal of the guide wire from the lumenof the catheter of FIG. 1b and the injection of an LCST material intothe kidney through the catheter.

[0034]FIG. 1d is similar to FIG. 1c except that FIG. 1d shows the kidneystone after being fragmented by, for example, a medical lithotripsydevice.

[0035]FIG. 1e illustrates the capture of a kidney stone fragment by amedical retrieval device such as a basket.

[0036]FIG. 1f shows the kidney after removal of the kidney stonefragments of FIGS. 1d and 1 e, and after some of the LCST material hasdrained and/or been removed from the body.

[0037]FIG. 2a illustrates the percutaneous insertion of a needle into akidney containing a kidney stone, with a syringe containing an LCSTmaterial connected to the needle on the outside of the patient's body.

[0038]FIG. 2b illustrates the injection of the LCST material from thesyringe, through the needle, and into the kidney.

[0039]FIG. 2c shows the kidney stone after being fragmented by, forexample, a medical lithotripsy device.

[0040]FIG. 2d illustrates the capture of a kidney stone fragment by amedical retrieval device such as a basket.

[0041]FIG. 2e shows the kidney after removal of the kidney stonefragments and after some of the LCST material has drained and/or beenremoved from the body.

DESCRIPTION

[0042] The invention generally relates to systems and methods forstabilizing objects (such as kidney stones, gall stones, and othernatural and foreign substances) found in the body of a patient (such asa human or other mammal) by the injection of a flowable material intothe patient's body and the transformation of the material into a gel.The gel contacts and thereby stabilizes the object in the patient'sbody. The invention involves using materials that become a gel at orabove about body temperature, materials that become a gel when contactedwith a crosslinking agent, and gelatin materials that form a gel attemperatures below about body temperature.

[0043] The materials that are the subject of the invention, such as theLCST materials that become a gel at or about body temperature, can beinjected into the patient's body in a liquid form. The injected materialonce reaching body temperature undergoes a transition from a liquid to agel. Objects that are contacted by the material become trapped entirelyor partially within the gel and thus stabilized in place in the body.Medical devices for breaking the object into fragments and/or retrieving(or otherwise eliminating) the object and any of its fragments from thebody can accomplish the breaking and/or removal more easily because thegel causes the object to be fixed in place and does not allow the objectto move freely about the cavity in which it is located in the body.Additionally, fragments of the object that result from breaking theobject with a suitable medical device (such as a laser lithotriptor)generally remain trapped at least partially within the gel, in that thegel also traps the fragments and prevents the scattering of fragmentswithin the body. Kidney stone fragments that remain in the body can formthe nuclei for the growth of other kidney stones.

[0044] LCST materials possess a lower critical solution temperature,which is the temperature at which LCST materials transition from liquidto gel form. Suitable LCST materials includepolyoxyethylene-polyoxypropylene (PEO-PPO) block copolymers. Twoacceptable compounds are Pluronic acid F127 and F108, which are PEO-PPOblock copolymers with molecular weights of 12,600 and 14,600,respectively. Each of these compounds is available from BASF of MountOlive, N.J. Pluronic acid F108 at 20-28% concentration in phosphatebuffered saline (PBS) is an example of a suitable LCST material. A morepreferable preparation is 22.5% Pluronic acid F108 in PBS. A preparationof 22% Pluronic acid F108 in PBS has an LCST of 37° C. Pluronic acidF127 at 20-35% concentration in PBS is another example of a suitableLCST material. A preparation of 20% Pluronic acid F127 in PBS has anLCST of 37° C. Low concentrations of dye (such as crystal violet),hormones, therapeutic agents, fillers, and antibiotics can be added tothe LCST material. For example, a cancer-treating agent such asendostatin can be carried by the LCST material and thus delivered insidethe body via the LCST material. In general, other PEO-PPO blockcopolymers that are LCST materials and that are biocompatible,biodegradable, and exist as a gel at body temperature and a liquid atbelow body temperature can also be used according to the presentinvention. The molecular weight of a suitable material (such as a blockcopolymer) can be, for example, between 5,000 and 25,000, and moreparticularly between 7,000 and 15,000, and, for the two specificcompounds identified above, 12,600 or 14,600.

[0045] Materials that include crosslinkable polymers and that become agel when contacted with a crosslinking agent may be used in accordancewith the invention. An embodiment of the invention relates to injectinga material including one or more crosslinkable polymers into thepatient's body, contacting the crosslinkable polymers with a materialincluding one or more crosslinking agents and enabling the gel tocontact an object in the body. The material including crosslinkablepolymer(s) may contact the material including crosslinking agent(s)before or after injection into the body. If the crosslinkable polymer(s)contact the crosslinking agent(s) before injection into the body, thenmixture of crosslinkable polymer(s) and crosslinking agent(s) should beinjected into the body prior to the crosslinking reaction occurring andthe transformation of the materials into gel form. Contacting the gelformed with crosslinkable polymer(s) with a de-crosslinking agentdissolves the gel and facilitates its removal. Once the gel isdissolved, it flows down the ureter and into the bladder to be expelledfrom the body with the urine. The gel may also be removed by extractionof the material through a catheter or a percutaneous access device suchas a needle.

[0046] Referring to FIG. 1a, distal end of a guide wire 108 is insertedinto the urinary tract until reaching the kidney 100. The guide wire 108can include a controllable tip for the purpose of directing the guidewire 108 along the urinary tract. The guide wire 108 could similarly beinserted into other tracts or passageways of the body. A stone 106 ispresent in the calyx 102 of the kidney 100. The stone 106 could also belocated in other locations of the kidney 100 such as the renal pelvis orother locations in the urinary tract such as the ureter 104.

[0047] In FIG. 1b, the guide wire 108 serves as a guide for theinsertion of the distal end of the catheter 110 into the kidney 100. Thecatheter 110 slides over the guide wire 108 with the guide wire 108located in the lumen of the catheter 110. The catheter 110 may extendinto the kidney so that the distal end of the catheter 110 is disposednear the kidney calyx 102 and the stone 106.

[0048] The guide wire 108 is then withdrawn from the lumen of thecatheter 110 and is removed from the body, thus leaving the catheter 110within the body. The lumen of the catheter 110, unobstructed by theguidewire 108, may transport material in flowable form from the outsideof the patient's body into the patient's body and the calyx 102, forexample. The LCST material 112, as an example of a material in aflowable form, starts external to the body and at a temperature belowbody temperature and thus in a liquid and flowable form. In someembodiments, the LCST material 112 could be cooled to a temperaturebelow ambient air temperature prior to injection to delay the timerequired for the injected LCST material 112 to reach body temperatureand form a gel, but such cooling generally is not required. A mechanism,such as an automated or human-operated syringe, can be used to force theLCST material 112 through the catheter 110 and into the kidney 100, asshown in FIG. 1c. The mechanism can be any suitable device that appliespressure to the LCST material 112 to force it in a liquid form throughthe catheter 10 and into the body to contact the object to bestabilized. The LCST material 112 then enters, as a liquid, areas of thekidney 100 including the calyx 102 and the renal pelvis. The LCSTmaterial 112 also generally flows into the ureter 104 and towards theurinary bladder, as depicted in FIG. 1c. As the temperature of the LCSTmaterial 112 inside the body rises toward body temperature, the LCSTmaterial 112 reaches its LCST and transitions into the gel phase. Anobject, like the stone 106, in contact with the LCST material 112 willbe at least partially enveloped by the gel and thus stabilized by thegel. The stabilization of the stone 106 allows for easier capture andretrieval of the stone 106 because the stone 106 is held in place by thegel 112. Additionally, the transition from liquid to gel can cause theLCST material 112 to form a seal or plug in the ureter 104 near therenal pelvis that allows the LCST material 112 to accumulate in thekidney 100 instead of draining out of the ureter 104.

[0049] The introduction of other materials in flowable form into thepatient's body is performed in substantially the same manner as theintroduction of LCST material 112 into the patient's body. Materialsused in accordance with the invention include crosslinkable polymers andcrosslinking agents, which catalyze the transformation of thecrosslinkable polymers from a flowable form into a gel form. Theresulting gel is formed of an insoluble network of the crosslinkablepolymers.

[0050] Crosslinkable polymers that may be suitable for use in theinvention include both ionically crosslinkable and non-ionicallycrosslinkable polymers. To be used in conjunction with thesecrosslinkable polymers, crosslinking agents that may be employed includeboth ionic crosslinking agents and non-ionic crosslinking agents,respectfully. Ionically crosslinkable polymers include anioniccrosslinkable polymers and cationic crosslinkable polymers that may beused in conjunction with anionic crosslinking agents and cationiccrosslinking agents, respectively.

[0051] The anionic or cationic crosslinkable polymers may include, butare not limited to, at least one polymer or copolymer such aspolyacrylic acids, polymethacrylic acid, alginic acid, pectinic acids,sodium alginate, potasium alginate, carboxy methyl cellulose, hyaluronicacid, heparin, carboxymethyl starch, carboxymethyl dextran, heparinsulfate, chondroitin sulfate, polyethylene amine, polysaccharides,chitosan, carboxymethyl chitosan, cationic starch or salts thereof.Illustrative examples of cationic crosslinking agents includepolycations such as calcium, magnesium, barium, strontium, boron,beryllium, aluminium, iron, copper, cobalt, lead, and silver ions.Illustrative examples of anionic crosslinking agents include polyanionssuch as phosphate, citrate, borate, succinate, maleate, adipate andoxalate ions, and, more broadly, anions derived from polybasic organicor inorganic acids. The anionic or cationic crosslinking agents caneither be a mono- or poly-charged ion.

[0052] The crosslinkable polymer also includes non-ionicallycrosslinkable polymers that are transformed from a flowable form to agel form by contact with non-ionic crosslinking agents. Non-ioniccrosslinking agents may also be used instead of or in addition to ioniccrosslinking agents with ionically crosslinkable polymer. Thus, a highercrosslinking density and improved mechanical properties, i.e., improvedstiffness, modulus, yield stress and strength, may be accomplished byadditionally subjecting the ionically crosslinkable polymer to non-ioniccrosslinking. For example, non-ionic crosslinking can be accomplished bytreatment with a chemical crosslinking agent which reacts with groupspresent in the polymer such that covalent bonds are formed connectingdifferent portions of the polymer or between polymer strands to form anetwork.

[0053] Suitable non-ionic crosslinking agents are polyfunctionalcompounds preferably having at least two functional groups reactive withone or more functional groups present in the polymer. The crosslinkingagent can contain one or more of carboxyl, hydroxy, epoxy, halogen,amino functional groups or hydrogen unsaturated groups. Illustrativenon-ionic crosslinking agents include di-vinylsulfone, polycarboxylicacids or anhydrides, polyamines, epihalohydrins, diepoxides,dialdehydes, diols, carboxylic acid halides, ketenes and like compounds.Illustrative crosslinkable polymers include those that possess organicacid functional groups that are covalently crosslinkable withpolyfunctional crosslinking agents. The covalent bonds between thecrosslinking agents and the hydrophilic polymers are susceptible tohydrolysis in the body, releasing water-soluble components.

[0054] One embodiment utilizes crosslinking agents that can formrelatively weak covalent crosslinking bonds, so that these bonds can bede-crosslinked within the body after a desired length of time. Forexample, polymers comprising covalent bonds that are easily hydrolysableat temperature and pH conditions inside the body can serve this purpose.Such polyfunctional covalent crosslinking agents include polyfunctionalaziridines, polyfunctional carbodiimides, polyisocyanate, glutaraldehydeor other polyfunctional crosslinkers wherein the functional groups arecapable of reacting with the organic acid groups, or any activated formsthereof.

[0055] Alginate is an example of an ionically crosslinkable polymer.Alginate is a heterogeneous group of linear binary co-polymer of 1-4linked β-D-mannuronic acid (M) and its C-5 epimer O-L-guluronic acid(G). The monomers are arranged in blockwise pattern along the polymerchain where mannuronic blocks (M blocks) and guluronic blocks (G blocks)are interspaced with sequences containing both M monomers and G monomers(mixed or MG blocks). The proportion and sequential arrangement of theuronic acids in alginate depend upon the species of algae and the kindof algal tissue from which the material is prepared. Commercialalginates are produced from sources including Laminaria hyperborea,Macrocystis pyrifera, Laminaria digitata, Ascophyllum nodosum, Laminariajaponica, Eclonia maxima, Lesonia negrescens and Saragassum sp.

[0056] Monovalent cation alginate salts, such as sodium or potassiumalginate, are water soluble. Most divalent cations, such as calcium,strontium, or barium, interact with alginate to form water insoluble butwater permeable gels. Because of the higher affinity of these divalentcations for guluronate compared with mannuronate blocks and because ofsteric considerations, cooperative binding of gelling divalent cationsto guluronate within guluronate blocks provides the primaryintermolecular crosslinking responsible for formation of stable alginategels. Mannuronate and mixed blocks are not crosslinked due to theirweaker affinity for the crosslinking divalent cation, but function asflexible interconnecting segments between interacted guluronate blocks.

[0057] Different divalent cations have different affinities formannuronate and guluronate and thus are differentially susceptible to bedisplaced by exchange with other monovalent or divalent cations.Likewise, depending on the molecular weight, the number of residues perblock and the overall ratio of guluronate to mixed or mannuronateblocks, different alginates have different susceptibilities to undergoion exchange reactions.

[0058] The degree of crosslinking, both ionic and non-ionic, can becontrolled mainly as a function of the concentrations of thecrosslinking agents and crosslinkable polymers, such as alginate forexample. The crosslinking agents and crosslinkable polymers may be in asolution of water or of another suitable solvent or mixture thereof. Thesolvent is not limited as long as it is suitable for the application. Insolution, the concentrations of the crosslinking agent or crosslinkablepolymers can range from about 0.0001 M to about 10 M and is to bedetermined according to the application.

[0059] In FIG. 1d, the stone 106 is shown broken apart into fragmentsand this fragmentation can be achieved generally by a medical devicethat delivers light, chemical, physical, or other type of energy to thestone 106. Intra-corporeal shock wave lithotripsy (ISWL) is a method offragmenting a stone 106 with vibrational energy produced by a deviceinternal to the patient's body. Energy transferred to stone may emanatefrom a device such as a fragmenting probe 111 placed inside thepatient's body and near the targeted stone 106 in order to fragment thestone 106. The fragmenting probe 111 is inserted into the patient's bodyuntil reaching the general area in which the stone 106 resides. Once thestone 106 is targeted by the fragmenting probe 111, an energy isreleased from the fragmenting probe 111 and is at least partly absorbedby the stone 106 causing the stone 106 to fragment into at least twofragments. The energy released from the fragmenting probe 111 may be inthe form of light from a Holmium laser, vibrational or shockwave energy,for example. The fragmenting probe 111 need not be inserted into thebody via the ureter 104, but may also be inserted percutaneously. Thefragmenting probe 111 may be removed from the patient's body once thefragmentation of the stone 106 is complete. Referring to FIGS. 2a-e, thefragmenting probe 111 is equally effective in the devices and methods inwhich the flowable material is injected into the patient's bodypercutaneously.

[0060] In FIG. 1e, a fragment or a whole stone 106 is captured by amedical retrieval device 114. The retrieval device 114 may be insertedinto the kidney 100 via the urinary tract or through the catheter 110 orin some other manner. The retrieval device 114 can be a basket. Thebasket or other stone capturing device makes contact with the stone 106and typically is manipulated by a human operator to ensnare the stone106. Once the stone 106 is captured, the device 114 can be withdrawnfrom the body in order to remove the stone 106. The capture and removalof stones 106 or stone fragments can be repeated by reinserting theretrieval device 114. The LCST material 112, or other material thatforms the gel, functions to stabilize the stones 106 or stone fragmentsduring the possible multiple rounds of stone removal thus preventingdispersal of stones 106 or stone fragments throughout the kidney 100.

[0061] In FIG. 1f, the retrieval device 114 has been withdrawn from thekidney 100. The LCST material 112 in gel form will break down and flushout of the body over time. To speed the removal of the gel from thebody, a chilled fluid can be introduced into the body, but such aprocedure generally is not required. If used, the fluid could be aphysiologically acceptable liquid such as water, saline, contrast media,or other fluid having temperature below the LCST of the LCST material112. The preferred temperature of the chilled fluid is, for example,−10° C. to 20° C., and more preferably 0° C. to 10° C. The fluid may bechilled by packing the fluid in ice, refrigerating the fluid or othermeans. The fluid could be introduced into the gel 112 through thecatheter 110. The catheter 110 can be used to remove (by, for example,suction) at least some of the LCST material 112, whether or not the gelis cooled to return it to its flowable liquid form. In one preferredembodiment, a cooling fluid is not used in either the delivery orremoval of the LCST material, and instead the gel is eliminatednaturally from the body over time. The catheter 110 could be anindependent tubular structure as shown. Alternatively, catheter 110could be incorporated as part of a medical device that is inserted intothe kidney 100 such as a tool that breaks apart the stone 106 orcollects stone fragments.

[0062] The material including crosslinkable polymers that forms a gelmay be dissolved to assist in the removal of the gel from the patient'sbody. The gel formed from crosslinkable polymers may include or beexposed to a de-crosslinking agent which functions by displacing acrosslinking agent within the network of crosslinkable polymers thatforms the gel. Suitable de-crosslinking agents include sodium phosphate,sodium citrate, inorganic sulfates, ethylene diamine tetraacetic acidand ethylene dime tetraacetate, citrates, organic phosphates (e.g.,cellulose phosphate), inorganic phosphates (e.g., pentasodiumtripolyphosphate, mono- and di-basic potassium phosphate, sodiumpyrophosphate), phosphoric acid, trisodium carboxymethyloxy succinate,nitrilotriacetic acid, maleic acid, oxalate, polyacrylic acid, sodium,potassium, calcium, or magnesium ions.

[0063] The de-crosslinking agent may be added to the gel using anappropriate technique. Methods for triggered de-crosslinking includeadministering or triggering release of the de-crosslinking agent throughthe diet, administering the de-crosslinking agent directly into the gelin an aqueous solution, encapsulating the de-crosslinking agent in thegel, and enema. Once the de-crosslinking agent comes in contact with thegel formed from crosslinkable polymers, the bonds between thecrosslinkable polymers that create the network that forms the gel willweaken or break causing the crosslinkable polymers to transform into aflowable form. Once in a flowable form the crosslinkable polymers canflow out of the patient's body via the ureter 104 and be extracted by acatheter 110 or a percutaneous access device such as a needle 118.

[0064]FIGS. 2a-e generally depict methods and systems of the inventionthat are similar to the methods and systems depicted in FIGS. 1a-f. Aprimary difference between the two sets of drawings is the way the LCSTmaterial 112 or other flowable materials that form a gel in thepatient's body is introduced into the patient's body. Referring to FIG.2a, a needle 118 is inserted percutaneously through the skin 116 andinto the body of the patient through the wall of the kidney 100 untilreaching the calyx 102. A stone 106 is present in the calyx 102 of thekidney 100. The stone 106 could also be located in other locations ofthe kidney 100 such as the renal pelvis or other locations in theurinary tract such as the ureter 104.

[0065] LCST material 112, similar to the methods and devices depicted inFIGS. 1a-e, is an example of the many types of materials that exist in aflowable form outside the patient's body and are transformed into gelform while in the patient's body. Such materials, that include thecrosslinkable polymers and gelatin materials previously described inFIGS. 1a-e, are equally applicable to the methods and devices describedin FIGS. 2a-e.

[0066] The LCST material 112 starts external to the body, at atemperature below body temperature and in a liquid and flowable form. Insome embodiments, the LCST material 112 could be cooled to a temperaturebelow ambient air temperature prior to injection to delay the timerequired for the injected LCST material 112 to reach body temperatureand form a gel, but such cooling generally is not required. A mechanism,such as an automated or human-operated syringe, can be used to force theLCST material 112, or other flowable materials, through the needle 118and into the kidney 100, as shown in FIG. 2b. The mechanism can be anysuitable device that applies pressure to the LCST material 112 to forceit in a liquid form through the needle 118 and into the body to contactthe object to be stabilized. The LCST material 112 then enters, as aliquid, areas of the kidney 100 including the calyx 102 and the renalpelvis. The LCST material 112 also generally flows into the ureter 104and towards the urinary bladder, as depicted in FIG. 2b. As thetemperature of the LCST material 112 inside the body rises toward bodytemperature, the LCST material 112 reaches its LCST and transitions intothe gel phase. An object, like the stone 106, in contact with the LCSTmaterial 112 will be at least partially enveloped by the gel and thusstabilized by the gel. The stabilization of the stone 106 allows foreasier capture and retrieval of the stone 106 because the stone 106 isheld in place by the gel 112. Additionally, the transition from liquidto gel can cause the LCST material 112 to form a seal or plug in theureter 104 near the renal pelvis that allows the LCST material 112 toaccumulate in the kidney 100 instead of draining out of the ureter 104.

[0067] In FIG. 2c, the stone 106 is shown broken apart into fragments,and this fragmentation can be achieved by a device that delivers light,chemical, physical, or other type of energy to the stone 106. Followingthe breaking apart of the stone 106, the fragments of the stone 106 donot disperse throughout areas of the kidney. The gel formed from theLCST material 112 generally does not allow the fragments to escape, andthe gel, retains and stabilizes the fragments. The gel generally absorbsat least some of the energy imparted to the stone 106 to cause it tobreak apart, and thus the gel prevents the fragments of stone 106 andthe stone 106 itself from dispersing throughout the kidney 100.

[0068] Additionally, energy transferred to the stone 106 may emanatefrom outside the patient's body, from a lithotripter 121 for example,and travel through the patient's body until reaching the stone 106targeted for fragmentation in a process called extracorporeal shock wavelithotripsy (ESWL). ESWL is a method of stone fragmentation commonlyused to treat kidney stone disease. Various lithotripters 121 andmethods exist for generating high-intensity, focused shock waves for thefragmentation of objects, such as kidney stones 106, inside a humanbeing and confined in a body liquid. A lithotripter 121 generating aspark gap discharge in water has been used to generate a shock wavewithin an ellipsoidal reflector, which couples and focuses the shockwave to fragment kidney stones 106 inside the patient's body.Lithotripters 121 also exist that use a coil and a mating radiator, inthe form of a spherical segment, to produce magnetically inducedself-converging shock waves that can be directed at a stone 106 withinthe patient's body. A lithotripter 121 also exists that featurespiezoelectric elements arranged in mosaic form on a spheroidal cap havealso been used to produce focused high-intensity shock waves at thegeometric center of the cap, where the stone 106 must be placed.

[0069] Following the fragmentation of the stone 106 by ESWL, forexample, the fragments of the stone 106 do not disperse throughout areasof the kidney. The gel formed from the LCST material 112 generally doesnot allow the fragments to escape, and the gel retains and stabilizesthe fragments. The gel generally absorbs at least some of the energyimparted to the stone 106 to cause it to break apart, and thus the gelprevents the fragments of stone 106 and the stone 106 itself fromdispersing throughout the kidney 100. ESWL is equally applicable to thesystem and methods described in FIGS. 1a-e.

[0070] In FIG. 2d, a fragment or a whole stone 106 is captured by amedical retrieval device 114. The retrieval device 114 may be insertedinto the kidney 100 via the urinary tract or through the catheter 110 orin some other manner. The retrieval device 114 may include a basket. Thebasket or other stone capturing device makes contact with the stone 106and typically is manipulated by a human operator to ensnare the stone106. Once the stone 106 is captured, the device 114 can be withdrawnfrom the body in order to remove the stone 106. The capture and removalof stones 106 or stone fragments can be repeated by reinserting theretrieval device 114. The LCST material 112 that forms the gel functionsto stabilize the stones 106 or stone fragments during the possiblemultiple rounds of stone removal thus preventing dispersal of stones 106or stone fragments throughout the kidney 100. Additionally, the needle118 may be used to extract both the LCST material 112 and the stonefragments 106.

[0071] In FIG. 2e, the retrieval device 114 has been withdrawn from thekidney 100. The LCST material 112 in gel form will break down and flushout of the body over time. To speed the removal of the gel from thebody, a chilled fluid can be introduced into the body, but such aprocedure generally is not required. If used, the fluid could be aphysiologically acceptable liquid such as water, saline, contrast media,or other fluid having temperature below the LCST of the LCST material112. The preferred temperature of the chilled fluid is, for example,−10° C. to 20° C., and more preferably 0° C. to 10° C. The fluid may bechilled by packing the fluid in ice, refrigerating the fluid or othermeans. The fluid could be introduced into the gel 112 through the needle118. Additionally, a catheter 110 can be used to remove (by, forexample, suction) at least some of the LCST material 112, whether or notthe gel is cooled to return it to its flowable liquid form. In onepreferred embodiment, a cooling fluid is not used in either the deliveryor removal of the LCST material, and instead the gel is eliminatednaturally from the body over time. The needle 118 could be anindependent tubular structure as shown. Alternatively, needle 118 couldbe incorporated as part of a medical device that is inserted into thekidney 100 such as a tool that breaks apart the stone 106 or collectsstone fragments.

[0072] The LCST material 112 used to stabilize an object in the body canalso function as a carrier for chemical compounds, drugs, hormones, dyesor other additives to enhance the effectiveness, safety or functionalityof the gel. The LCST gel mixture may include a dye to aid in determiningthe presence of the LCST material 112. The LCST gel mixture can alsoinclude antibiotics and anti-microbial agents, and such a mixture mayassist in protecting the kidney against infection as a result of aninvasive surgical procedure. The LCST gel mixture can also include oneor more anti-inflammatory agents, which may assist in preventinginflammation in the kidney as a result of an invasive surgicalprocedure. Anesthetic agents may also be included in the LCST mixture inorder to assist in numbing the pain associated with the surgicalprocedure. The LCST material 112 can also contain therapeutic agents.The therapeutic agents may include anti-angiogenic agents such asendostatin, angiostatin and thrombospondin. A LCST mixture containinganti-angiogenic agents could be used to treat cancerous tumors.

[0073] The catheter 110 can be used to dispense one or more fluids otherthan or in addition to the LCST material. The catheter 110 also can be adilatation catheter with the ability also to dispense one or more fluidsother than or in addition to the LCST material. In one embodiment, thecatheter 110 is 4-8 french in size, and more preferably 5-6 french.

[0074] The syringe or other mechanism used to inject the LCST material112 in liquid form into the body can be, for example, a 5-100 cc syringesuch as a syringe with volume of 5-30 cc or with a volume of 5-10 cc.Pressure applied to the syringe can be applied by hand or by anautomated syringe pusher.

[0075] While the invention has been described above mainly in connectionwith the stabilization and then removal and/or fragmentation of a kidneystone, the invention has applicability to object stabilization, removal,and fragmentation generally. A variety of stones and other objects,other than kidney stones, can be acted on in accordance with theinvention, such as gall stones and biliary stones. Also, a variety oflocations within the body of a patient can be accessed and treatedaccording to the invention, such as other parts of the male or femaleurinary system, the gastrointestinal system, the biliary system, and thepancreatic duct.

[0076] It will be apparent to those skilled in the art that variousmodifications and variations can be made to the above-describedstructure and methodology without departing from the scope or spirit ofthe invention.

What is claimed is:
 1. A method for stabilizing an object in a patient'sbody comprising: injecting a first material comprising a crosslinkablepolymer in a flowable form into the patient's body to contact an object;contacting the first material with a second material comprising acrosslinking agent, the first material and second material, uponcontact, forming a gel in the patient's body; and stabilizing the objectin the patient's body by enabling the gel to contact the object.
 2. Themethod of claim 1 wherein the first material comprises one or more of ananionic crosslinkable polymer, a cationic crosslinkable polymer, or anon-ionically crosslinkable polymer.
 3. The method of claim 1 whereinthe first material comprises one or more of polyacrylic acids,polymethacrylic acid, alginic acid, pectinic acids, sodium alginate,potasium alginate, carboxy methyl cellulose, hyaluronic acid, heparin,carboxymethyl starch, carboxymethyl dextran, heparin sulfate,chondroitin sulfate, polyethylene amine, polysaccharides, chitosan,carboxymethyl chitosan, cationic starch or salts thereof.
 4. The methodof claim 1 wherein the second material comprises one or more of ananionic crosslinking ion, a cationic crosslinking ion, or a non-ioniccrosslinking agent.
 5. The method of claim 1 wherein the second materialcomprises one or more of phosphate, citrate, borate, succinate, maleate,adipate, oxalate, calcium, magnesium, barium, strontium, boron,beryllium, aluminium, iron, copper, cobalt, lead, or silver ions.
 6. Themethod of claim 1 wherein the second material comprises one or more ofdi-vinylsulfone, polycarboxylic acids, polycarboxylic anhydrides,polyamines, epihalohydrins, diepoxides, dialdehydes, diols, carboxylicacid halides, ketenes, polyfunctional aziridines, polyfunctionalcarbodiimides, polyisocyanate, glutaraldehyde, or polyfunctionalcrosslinkers including functional groups capable of reacting withorganic acid groups.
 7. The method of claim 1 further comprising thestep of retrieving the object from the gel.
 8. The method of claim 1further comprising the step of applying energy to the object causing itto break into at least two fragments, at least some of the fragmentsremaining at least partially in contact with the gel and stabilized bythe gel.
 9. The method of claim 8 wherein the energy is selected fromthe group consisting of mechanical, vibrational, light, chemical, andelectromagnetic energy.
 10. The method of claim 8 wherein the object isbroken into at least two fragments by technique selected from the groupconsisting of extra-corporeal shock wave lithotripsy, intra-corporealshock wave lithotripsy, or Holmium laser fragmentation.
 11. The methodof claim 8 further comprising the step of retrieving at least some ofthe fragments from the gel.
 12. The method of claim 11 wherein the stepof retrieving at least some of the fragments from the gel includes usinga retrieval device to retrieve such fragments.
 13. The method of claim 1further comprising contacting the gel with a third material comprising ade-crosslinking agent.
 14. The method of claim 13 wherein the thirdmaterial comprises one or more of sodium phosphate, sodium citrate,inorganic sulfates, ethylene diamine tetraacetic acid and ethylene dimetetraacetate, citrates, organic phosphates (e.g., cellulose phosphate),inorganic phosphates (e.g., pentasodium tripolyphosphate, mono- anddi-basic potassium phosphate, sodium pyrophosphate), phosphoric acid,trisodium carboxymethyloxy succinate, nitrilotriacetic acid, maleicacid, oxalate, polyacrylic acid, sodium, potassium, calcium, ormagnesium ions.
 15. A method of fragmenting an object in a patient'sbody comprising: injecting a material in a flowable form into thepatient's body to contact an object; allowing the material to form a gelin the patient's body; stabilizing the object in the patient's body byenabling the gel to contact the object; and applying energy from outsideof the patient's body directed towards the object, the energy breakingthe object into at least two fragments.
 16. The method of claim 15wherein the energy is produced by extra-corporeal shock wavelithotripsy.
 17. The method of claim 15 wherein the material comprisesone or more of a crosslinkable polymer, a gelatin material or a lowercritical solution temperature material.
 18. The method of claim 15wherein the material comprises a polyoxyethylene-polyoxypropylene blockcopolymer.
 19. The method of claim 15 further comprising the step ofretrieving the stabilized object from the gel.
 20. The method of claim15 further comprising the step of breaking the object into at least twofragments, at least some of the fragments remaining in contact with thegel.
 21. The method of claim 20 further comprising the step ofretrieving the at least some of the fragments from the gel.
 22. Themethod of claim 15 further comprising contacting the lower criticalsolution temperature material with a degradation modulating material.23. The method of claim 22 wherein the degradation modulating materialis selected from the group consisting of pluronic acid, polylactic acid,polyglycolic acid, and hyaluronic acid.
 24. A system for stabilizing anobject in a patient's body comprising: a first material comprising acrosslinkable polymer in flowable form; a second material comprising acrosslinking agent, such that the first material and second material,upon contact, form a gel in the patient's body; a catheter fortransferring the first material and second material into the patient'sbody in flowable form, such that the gel formed by the first materialand second material contacts and thereby stabilizes the object; and aguide wire for introducing and guiding the catheter into the patient'sbody.
 25. The system of claim 24 wherein the first material comprisesone or more of an anionic crosslinkable polymer, a cationiccrosslinkable polymer, or a non-ionically crosslinkable polymer.
 26. Thesystem of claim 24 wherein the first material comprises one or more ofpolyacrylic acids, polymethacrylic acid, alginic acid, pectinic acids,sodium alginate, potasium alginate, carboxy methyl cellulose, hyaluronicacid, heparin, carboxymethyl starch, carboxymethyl dextran, heparinsulfate, chondroitin sulfate, polyethylene amine, polysaccharides,chitosan, carboxymethyl chitosan, cationic starch or salts thereof. 27.The system of claim 24 wherein the second material comprises one or moreof an anionic crosslinking ion, a cationic crosslinking ion, or anon-ionic crosslinking agent.
 28. The system of claim 24 wherein thesecond material comprises one or more of phosphate, citrate, borate,succinate, maleate, adipate, oxalate, calcium, magnesium, barium,strontium, boron, beryllium, aluminium, iron, copper, cobalt, lead, orsilver ions.
 29. The system of claim 24 wherein the second materialcomprises one or more of di-vinylsulfone, polycarboxylic acids,polycarboxylic anhydrides, polyamines, epihalohydrins, diepoxides,dialdehydes, diols, carboxylic acid halides, ketenes, polyfunctionalaziridines, polyfunctional carbodiimides, polyisocyanate,glutaraldehyde, or polyfunctional crosslinkers including functionalgroups capable of reacting with organic acid groups.
 30. A system forstabilizing an object in a patient's body comprising: a first materialcomprising a crosslinkable polymer; a second material comprising acrosslinking agent, such that the first material and second material,upon contact, form a gel in the patient's body; and a percutaneousaccess device for injecting the first material and second material intothe patient's body in flowable form, such that the gel formed by thefirst material and second material contacts and thereby stabilizes theobject.
 31. The system of claim 30 wherein the first material comprisesone or more of an anionic crosslinkable polymer, a cationiccrosslinkable polymer, or a non-ionically crosslinkable polymer.
 32. Thesystem of claim 30 wherein the first material comprises one or more ofpolyacrylic acids, polymethacrylic acid, alginic acid, pectinic acids,sodium alginate, potasium alginate, carboxy methyl cellulose, hyaluronicacid, heparin, carboxymethyl starch, carboxymethyl dextran, heparinsulfate, chondroitin sulfate, polyethylene amine, polysaccharides,chitosan, carboxymethyl chitosan, cationic starch or salts thereof. 33.The system of claim 30 wherein the second material comprises one or moreof an anionic crosslinking ion, a cationic crosslinking ion, or anon-ionic crosslinking agent.
 34. The system of claim 30 wherein thesecond material comprises one or more of phosphate, citrate, borate,succinate, maleate, adipate, oxalate, calcium, magnesium, barium,strontium, boron, beryllium, aluminium, iron, copper, cobalt, lead, orsilver ions.
 35. The system of claim 30 wherein the second materialcomprises one or more of di-vinylsulfone, polycarboxylic acids,polycarboxylic anhydrides, polyamines, epihalohydrins, diepoxides,dialdehydes, diols, carboxylic acid halides, ketenes, polyfunctionalaziridines, polyfunctional carbodiimides, polyisocyanate,glutaraldehyde, or polyfunctional crosslinkers including functionalgroups capable of reacting with organic acid groups.